bims-tumhet 2023-05-28 papers

Issue of 2023‒05‒28
four papers selected by
Sergio Marchini
Humanitas Research

Ther Adv Med Oncol. 2023 ;15 17588359231173183

The role of PARP inhibitor combination therapy in ovarian cancer.

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

Keywords: PARP inhibitor; angiogenesis; combination therapy; epithelial ovarian cancer; homologous recombination deficiency

DOI: https://doi.org/10.1177/17588359231173183

Ann Oncol. 2023 May 19. pii: S0923-7534(23)00686-5. [Epub ahead of print]

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

PAOLA-1/ENGOT-ov25 investigators

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.PATIENTS AND METHODS: Patients were randomized 2:1 to olaparib (300 mg bid; up to 24 months) plus bevacizumab (15 mg/kg q3w; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.
RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the ITT (hazard ratio [HR]=0.92, 95% CI 0.76-1.12; P=0.4118). Subsequent poly(ADP-ribose) polymerase (PARP) inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR=0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR=0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.
CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving PARP inhibitors post-progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Keywords: advanced ovarian cancer; bevacizumab; olaparib; overall survival

DOI: https://doi.org/10.1016/j.annonc.2023.05.005

Cell Rep Med. 2023 May 16. pii: S2666-3791(23)00169-6. [Epub ahead of print] 101055

Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Paula Cunnea, Edward W Curry, Elizabeth L Christie, Katherine Nixon, Chun Hei Kwok, Ahwan Pandey, Ratri Wulandari, Kerstin Thol, Jennifer Ploski, Cristina Morera-Albert, Stephen McQuaid, Jingky Lozano-Kuehne, James J Clark, Jonathan Krell, Euan A Stronach, Iain A McNeish, David D L Bowtell, Christina Fotopoulou.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.

Keywords: Cyclin E1; HRD; cytoreductive surgery; high-grade serous ovarian cancer; homologous recombination deficiency score; spatial and temporal heterogeneity; tumor evolution

DOI: https://doi.org/10.1016/j.xcrm.2023.101055

Signal Transduct Target Ther. 2023 May 22. 8(1): 210

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets.

Jing Yang, Jin Xu, Wei Wang, Bo Zhang, Xianjun Yu, Si Shi.

Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed.

DOI: https://doi.org/10.1038/s41392-023-01480-x